Dace Reihmane

Interleukin-6: Possible biological roles during exercise

Abstract Interleukin-6 (IL-6) is a multifunctional cytokine that exerts its modulatory effects on cells that express membrane bound IL-6 receptors; however, IL-6 in a complex with soluble IL-6R can bind to any cell that express glycoprotein 130 (gp130). Thus, all cell types may respond to the pro- as well as anti-inflammatory properties of IL-6. Since the first report of acute exercise-induced increase in plasma IL-6 in the early 1990s, scientists have tried to elucidate the factors that influence the magnitude of change of plasma IL-6, as well as the possible biological roles of this cytokine. Evidence suggests that exercise intensity and duration as well as the form of contraction (e.g. eccentric or concentric) and muscle damage all influence IL-6 response to acute exercise. However, data on training status and performance on plasma IL-6 concentration changes during exercise are more inconclusive, as discussed in this review. In the last decade, most of the studies have focused on IL-6 as an ‘energy sensor’ possibly secreted by skeletal muscle that activates glycogenolysis in the liver and lipolysis in fat tissue in order to provide muscle with the growing energy demands during exercise.

The Relationship Between Maximal Exercise-Induced Increases in Serum IL-6, MPO and MMP-9 Concentrations

The aim of this study was to test the hypothesis that exercise would induce inflammatory response characterized by increased pro‐inflammatory cytokines – interleukin‐6 (IL‐6) and tumour necrosis factor‐α (TNF‐α), adhesion molecule, matrix metalloprotease‐9 (MMP‐9) and myeloperoxidase (MPO) levels. Additional aim was to elucidate the possible source of maximal exercise‐induced increase in MMP‐9 concentration. To examine our hypothesis, 26 professional male ice hockey players [age 25 ± 1 (mean ± SEM) years; BMI 25.8 ± 0.4 kg/m2] performed an incremental bicycle test until exhaustion, when maximal oxygen consumption was recorded. Venous blood samples were collected 30 min before and 2 min after exercise. There was an increase in the count of leucocytes (8.7 ± 1.8 versus 5.7 ± 1.3 × 109 cells per l) and IL‐6 (1.24 ± 0.17 versus 0.69 ± 0.13 pg/ml), MPO (72 ± 7 versus 50 ± 4 ng/ml) and MPP‐9 (139 ± 9 versus 110 ± 6 ng/ml) concentrations (P < 0.05) comparing post‐ and pre‐exercise levels. Maximal exercise‐induced increase in MPO correlated with the increases in IL‐6 (P < 0.05, R = 0.54) and MMP‐9 (P < 0.01, R = 0.62) concentrations. Furthermore, increase in IL‐6 correlated with the increase in MMP‐9 concentrations (P < 0.05, R = 0.60). Maximal exercise induces an inflammatory response characterized by leucocytosis and increased IL‐6, MPO and MMP‐9 concentrations. Correlations between increased MPO (marker of neutrophils degranulation) and both increased IL‐6 and MMP‐9 concentrations may suggest that neutrophils could be the main source of these inflammatory biomarkers during maximal exercise. Furthermore, correlation between increases in serum IL‐6 and MMP‐9 concentrations may suggest that IL‐6 could exert modulatory effects on MMP‐9 release during maximal exercise.

Circulating adhesion molecules, matrix metalloproteinase-9, plasminogen activator inhibitor-1, and myeloperoxidase in coronary artery disease patients with stable and unstable angina

BACKGROUND There are many pathophysiological mechanisms underlying reciprocal relationships between changes in cytokines and insulin resistance in metabolic and cardiovascular disorders. The aim of this study was to evaluate alterations in soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), matrix metalloproteinase-9 (MMP-9), plasminogen activator inhibitor-1 (PAI-1), and myeloperoxidase (MPO) levels, and their relation to insulin resistance in coronary artery disease (CAD) patients with stable and unstable angina (SAP, UAP). METHODS Non-diabetic CAD patients were classified into two groups: 22 patients with SAP and 22 patients with UAP. 22 healthy subjects were selected as controls. The study groups were matched for age and sex. Insulin resistance was evaluated by HOMA-IR method. Serum levels of sICAM-1, sVCAM-1, sE-selectin PAI-1(total), MPO and MMP-9 were quantified by xMAP technology (Luminex-200 analyzer). RESULTS Both patient groups demonstrated significantly elevated serum levels of sICAM-1, sE-selectin, PAI-1(total), MPO and MMP-9 (p<0.05) as well as higher IR-HOMA values (p<0.05) than those of healthy controls. The elevation was more pronounced in the UAP group (p<0.01). HOMA-IR was correlated with sICAM-1, PAI-1(total), and MMP-9 (p<0.01). CONCLUSION Our findings show that CAD patients have elevated HOMA-IR values. Furthermore, CAD patients with UAP have higher levels of sICAM-1, sVCAM-1, sE-selectin, MMP-9, PAI-1(total), and MPO than patients with SAP, and there are relationships between three of the above biomarkers: sICAM-1, PAI-1(total), MMP-9 and HOMA-IR.

Relation of inflammatory chemokines to insulin resistance and hypoadiponectinemia in coronary artery disease patients

BACKGROUND Although many studies have shown that the metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) both are associated with chronic inflammatory state and are risk factors for coronary artery disease (CAD), it is still unclear which condition is a more important contributor to the increased production of inflammatory chemokines. The purpose of this study was to assess monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) levels and their association with insulin resistance and adiponectin concentrations in CAD patients, who were categorized as having T2DM, MS, or neither. METHODS CAD male patients were categorized into three groups: 24 non-obese patients with T2DM (D), 24 obese patients with MS (M) and 24 patients without T2DM or MS (W). 20 healthy subjects were selected as controls (C). Insulin resistance was assessed by the HOMA-IR method, but serum MCP-1, IL-8, and adiponectin levels were measured by xMAP technology. RESULTS Serum levels of MCP-1 and IL-8 in D and M groups were increased in comparison with W and C groups (p<0.001, p<0.01), but the increase in the M group was significantly higher than that in the D group (p<0.05, p<0,001), besides MCP-1 and IL-8 concentrations were correlated with HOMA-IR indexes (r=0.52; r=0.49, p<0.0001) and adiponectin levels (r=-0.59, p<0.0001). The M group demonstrated a diminution in the adiponectin level (p<0.01) and pronounced increase of HOMA-IR in comparison with the other three groups (p<0.01). CONCLUSION Obese CAD patients with MS have a more pronounced increase of MCP-1, IL-8 and HOMA-IR and more decreased adiponectin levels than non-obese CAD patients without MS.

Immobilization increases interleukin‐6, but not tumour necrosis factor‐α, release from the leg during exercise in humans

•  What is the central question of this study? Does physical inactivity influence the exercise‐induced release of tumour necrosis factor‐α and interleukin‐6 in healthy humans? In young, healthy subjects, we immobilized one leg for 2 weeks, followed by 45 min two‐legged exercise where one leg served as the control and the other was the previously inactive leg. •  What is the main finding and its importance? We found that prior physical inactivity enhances interleukin‐6 release during exercise, and it is released in the blood from the legs during exercise much faster than previously known. However, tumour necrosis factor‐α is not released in the blood with exercise, even from a previously inactive leg.

Exercise promotes IL-6 release from legs in older men with minor response to unilateral immobilization

Abstract Physical inactivity is a major contributor to low-grade systemic inflammation. Most of the studies characterizing interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) release from exercising legs have been done in young, healthy men, but studies on inactivity in older people are lacking. The impact of 14 days of one-leg immobilization (IM) on IL-6 and TNF-α release during exercise in comparison to the contralateral control (CON) leg was investigated. Fifteen healthy men (age 68.1 ± 1.1 year (mean ± SEM); BMI 27.0 ± 0.4 kg·m2; VO2max 33.3 ± 1.6 ml·kg‒1·min‒1) performed 45 min of two-leg dynamic knee extensor exercise at 19.5 ± 0.9 W. Arterial and femoral venous blood samples from the CON and the IM legs were collected every 15 min during exercise, and thigh blood flow was measured with ultrasound Doppler. Arterial plasma IL-6 concentration increased with exercise (rest vs. 45 min, main effect p < .05). IL-6 release increased with exercise (rest vs. 30 min, main effect p < .05). Furthermore, IL-6 release was borderline (main effect, p = .085, effect size 0.28) higher in the IM leg compared to the CON leg (288 (95% CI: 213–373) vs. 220 (95% CI: 152–299) pg·min‒1, respectively). There was no release of TNF-α in either leg and arterial concentrations remained unchanged during exercise (p > .05). In conclusion, exercise induces more pronounced IL-6 secretion in healthy older men. Two weeks of unilateral immobilization on the other hand had only a minor influence on IL-6 release. Neither immobilization nor exercise had an effect on TNF-α release across the working legs in older men.

Neopterin, cellular adhesion molecules and myeolperoxidase in patients with stable and unstable angina pectoris

Neopterin, cellular adhesion molecules and myeolperoxidase in patients with stable and unstable angina pectoris Recent data indicate that the serum level of neopterin, a marker of inflammation and immune modulator secreted by monocytes/macrophages, is elevated in patients with acute coronary syndrome (ACS) and seems to be a prognostic marker for major cardiovascular events. Soluble cellular adhesion molecules (sCAMs) and myeloperoxidase (MPO) levels are also related to ACS. The aim of the present study was to evaluate differences in serum levels of neopterin, sCAMs and MPO between coronary artery disease and metabolic syndrome (CAD-MetS) patients with stable and unstable angina pectoris (SAP, UAP), and to clarify the relationships between neopterin and other biomarkers. The study included 60 patients with CAD-MetS who were classified into two groups, 30 patients with SAP and 30 patients with UAP. Twenty healthy subjects were selected as controls (C). Serum soluble vascular cell adhesion molecule-1 (sVCAM-1), intercellular cell adhesion molecule-1 (sICAM-1), sE-selectin and MPO levels were measured by Luminex xMAP technology, and serum neopterin concentrations were measured by radioimmunoassay. Results: Serum levels of neopterin, MPO, sVCAM-1, sICAM-1, and sE-selectin were significantly higher in patients with UAP in comparison with the group of healthy controls (P < 0.05). Patients with SAP also had higher levels of these biomarkers than those in healthy controls (P < 0.05), except for sE-selectin. The biomarker level did not differ between the two patient groups, except for MPO, which was significantly higher in the USP group (P < 0.05). Neopterin was significantly correlated only with sVCAM-1 (P < 0.05). In conclusion, CAD-Met patients with SAP had more apparent raised levels of serum sICAM-1 and sVCAM-1, simultaneously with higher MPO and neopterin concentrations, in comparison to those in healthy subjects. However, UAP is also associated with more substantial changes in MPO and significantly increased sE-selectin levels. Neopterin concentration was had a close correlation only with sVCAM-1. Neopterīns, šūnu adhēzijas molekulas un mieloperoksidāze pacientiem ar stabilu un nestabilu stenokardiju Mūsdienu pētījumi liecina, ka pacientiem ar akūtu koronāro sindromu (ACS) ir palielināta neopterīna koncentrācija asins serumā un tā spēj kalpot kā prognostisks biomarķieris kardiovaskulāriem notikumiem. Seruma šķīstošo šūnu adhēzijas molekulu (sCAMs) un mieloperoksidāzes (MPO) koncentrācijas palielināšanās arī ir saistīta ar ACS. Šī pētījuma mērķis bija novērt¯t atšķirības neopterīna, sCAMs un MPO seruma koncentrāciju atšķirības koronārās sirds slimības un metabolā sindroma pacientiem (CAD-MetS) ar stabilu un nestabilu stenokardiju (SAP, UAP), kā arī noskaidrot neopterīna saistību ar minētajiem biomarķieriem. Pētījumā tika iesaistīti 60 CAD-MetS pacienti, no kuriem 30 bija ar SAP un 30 ar UAP. 20 veseli voluntieri tika iekļauti kontroles grupā (C). Seruma šķīstošo vaskulāro šūnu adhēzijas molekulu-1 (sVCAM-1), intracelulāro šūnu adhēzijas molekulu-1(sICAM-1), šķīstošā E-selektīna (sE-selectin) un MPO koncentrācijas tika noteiktas ar Luminex xMAP tehnologiju, bet seruma neopterīna koncentrācija - radioimunologiski. Seruma neopterīna, MPO, sVCAM-1, sICAM-1 un sE-selectin koncentrācijas bija statistiski ticami augstākas pacientiem ar UAP, salīdzinot ar C grupu (P < 0.05). Pacientiem ar SAP arī bija būtiski augstāka minēto biomarķieru koncentrācija serumā nekā veseliem voluntieriem, izņemot sE-selectin koncentrācijas, kas neatšķīrās. Pētījuma biomarķieru koncentrācijas neatšķīrās starp pacientu grupām, izņemot MPO koncentrāciju, kas bija būtiski lielāka USP pacientu grupā (P < 0.05). Neopterīna koncentrācijas būtiski korelēja tikai ar sVCAM-1 koncentrācijām (P < 0.05). Tādējādi CAD-MetS pacientiem ar SAP ir būtiskāk izteikts sVCAM-1 un sICAM-1 seruma koncentrāciju palielinājums, vienlaikus, lielākas neopterīna un MPO koncentrācijas, bet UAP saistīts ar vēl būtiskāku MPO un sE-selectin koncentrāciju palielināšanos, salīdzinot ar veseliem voluntieriem. Seruma neopterīnam ir cieša korelācija tikai ar sVCAM-1.

Relation of Endothelial Dysfunction and Adipokines Levels to Insulin Resistance in Metabolic Syndrome Patients

Relation of Endothelial Dysfunction and Adipokines Levels to Insulin Resistance in Metabolic Syndrome Patients Obese metabolic syndrome (MS) patients were categorised into three groups: 44 with type 2 diabetes mellitus (T2DM)(D); 20 with T2DM and coronary artery disease (CAD) (DC), and 26 with MS alone (M). Eighteen healthy subjects were selected as controls (C). Insulin resistance (IR) was assessed by HOMA-IR. Adiponectin, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8) concentrations were measured by xMAP technology. Endothelin-1 (ET-1) was determined by ELISA. We used laser Doppler imaging for evaluating cutaneous endothelium-dependent vasodilatation in the hand. D and DC groups had significantly elevated IR compared with M or C group (P < 0.01). TNF-α, IL-6, IL-8, MCP-1 and ET-1 levels in DC were significantly elevated compared with other groups (P < 0.001). IL-6, IL-8, MCP-1 and ET-1 in D group were higher than those in C group (P < 0.05). TNF-α, IL-6, IL-8, MCP-1 and ET-1 concentrations were correlated with HOMA-IR indexes and adiponectin levels. All patients had lower adiponectin concentrations than controls (P < 0.001), but there were no differences between the patient groups. Only D and DC groups demonstrated a significant and similar decrease in LDI-Ach marker compared to C group (P < 0.001). LDI-Ach values were significantly correlated with HOMA-IR indexes and adiponectin levels (P < 0.001). Our findings show that obese MS patients have significantly increased HOMA-IR, TNF-α, IL-6, MCP-1 and IL-8 levels, decreased adiponectin concentration, and endothelial dysfunction, but the presence of T2DM and CAD in these patients is associated with more pronounced endothelial dysfunction and increased production of inflammatory cytokines and chemokines. Endoteliālās Disfunkcijas Un Adipokīnu Pārmaiņu Saistība Ar Insulīna Rezistenci Metabolā Sindroma Pacientiem Pētījumā iesaistītie metabolā sindroma (MS) pacienti, tika iedalīti sekojošās grupās: 26 pacienti ar MS (M), 44 ar 2-tipa cukura diabētu (T2DM) (D) un 20 ar T2DM un koronāro sirds slimību (CAD). Astoņpadsmit veseli cilvēki izveidoja kontroles grupu (C). Insulīna rezistence (IR) tika novērtēta ar HOMA-IR. Adiponektīna, tumoru nekrozes faktora-alfa (TNF-α), interleikīna-6 (IL-6), monocītu hemoatraktantā proteīna-1 (MCP-1) un interleikīna-8 (IL-8) koncentrāciju noteikšanai izmantojām xMAP tehnologiju, bet endotelīna-1 (ET-1) koncentrāciju noteicām ar ELISA. Lai novērtētu endotēlija-atkarīgo vazodilatāciju plaukstas ādā, izmantojām lāzerdoplerogrāfijas attēldiagnostiku kopā ar 1% acetilholīna transdermālu jontoforēzi (LDI-Ach). D un DC grupā IR bija būtiski lielāka, salīdzinot ar M un C grupu (P < 0.01). TNF-α, IL-6, IL-8, MCP-1 un ET-1 koncentrācijas DC grupā bija būtiski lielākas, salīdzinot ar visām pārējām pētījuma grupām (P < 0.001), bet IL-6, IL-8, MCP-1 un ET-1 koncentrācija D grupā būtiski atšķīrās no koncentrācijas C grupā (P < 0.05). Turklāt TNF-α, IL-6, IL-8, MCP-1 un ET-1 koncentrācijas statistiski ticami korelēja ar HOMA-IR rādītāju un adiponektīna koncentrāciju. Adiponektīna koncentrācijas neatšķīrās starp pacientu grupām, bet bija būtiski zemākas, salīdzinot ar kontroles grupu (P < 0.001). Vienīgi D un DC grupā bija būtisks un līdzīgs LDI-Ach rādītāja samazinājums (P < 0.001). Rādītāju LDI-Ach un HOMA-IR vērtības savstarpēji būtiski korelēja (P < 0.001). Mūsu pētījuma rezultāti liecina, ka adipoziem MS pacientiem būtiski pieaug IR un TNF-α, IL-6, IL-8 un MCP-1 koncentrācijas, bet samazinās adiponektīna koncentrācijas, un ir endoteliālā disfunkcija (palielinātas ET-1 koncentrācijas un samazināta LDI-Ach), savukārt, T2DM un CAD klātbūtne šiem pacientiem saistīta ar vairāk izteiktu endoteliālo disfunkciju un iekaisuma citokīnu un hemokīnu pieaugumu.

587 VASOMOTOR DYSFUNCTION AND ALTERATIONS OF CIRCULATING CYTOKINES IN DIABETIC POLYNEUROPATHY PATIENTS WITH AND WITHOUT MECHANICAL ALLODYNIA

(1.7±1.8; n = 43; per protocol) and the group treated vice versa (2.5±1.6; n =57; per protocol). These trends were supported by the results of the NPSI, SF-McGill, and allodynia severity rating. Combination therapy with 5% lidocaine medicated plaster and pregabalin did not have clinically relevant effects on laboratory parameters or vital signs. The overall incidence of discontinuations due to drug-related AEs was low. No drug-related SAE was reported during combination therapy. Conclusions: Results of this study demonstrate that 5% lidocaine medicated plaster is an efficacious combination partner. Patients with PHN or painful DPN experiencing insufficient efficacy during monotherapy with either pregabalin or lidocaine plaster can benefit from combination therapy. Funded by Grünenthal